The present invention relates to a therapeutic agent for Non-Insulin-Dependent Diabetes Mellitus (NIDDM).
Diabetes is mainly classified to two types, i.e. Insulin-Dependent Diabetes Mellitus (IDDM) and NIDDM (ref. Kosaka J., "The classification of disease based on the concept of Diabetes Mellitus", Nippon Rinsho 1990 extra number, Diabetes Mellitus, Nippon Rinsho Press, Osaka 1990, p. 161-168). IDDM is a severe disease which attacks mainly the infant with symptoms of polyuria or polyposia suddenly. Since a patient with IDDM suffers from an absolute deficiency of insulin, he dies due to ketosis unless he is added an adequate quantity of insulin.
On the other hand, NIDDM is Diabetes showing relative slight symptoms, which attacks slowly the overweight adult. The number of patient with NIDDM is large and it is said that in Japan more than 90% of patients who suffer from Diabetes show NIDDM and the number of them is two million.
IDDM and NIDDM are different in their causes. It was shown by studies using IDDM model animals such as NOD mouse-or BB rat that .beta.-cells in the pancreas which produce insulin are selectively killed by autoimmune in IDDM (ref. Satoh J., "Diabetes and immunity", Diabetes Frontier 1, 9-22 (1990)). Furthermore, it was reported that in these animals various immunotherapies related to processes of immune responses, such as an introduction of a normal gene of class II histocompatibility antigen, an enucleation of thymus, a transplant of normal bone marrow, an administration of various antibodies against T-cell or an administration of non-specific immunosuppressive agent, suppress a development of Diabetis, and furthermore, applications of their therapies to human IDDM have been progressing (ref. Satoh J. et al, "Current status of prevention and treatment of diabetic complications", Elsevier Science Publishers BV, Amsterdam, 1990, p. 658-661).
The present inventors have found that a nonspecific immune stimulation by an administration of immunopotentiator (ref. Toyota T. et al, Diabetes 35, 496-499 (1988) and Satoh J. et al, Diabetes 37, 1188-1194 (1988)) or by an administration of lymphotoxin (LT) (ref. Satoh J. et al., Japanese Unexamined Patent Publication No. 112835/1992 and Seino H. et al, Diabetes (in press)) or tumour necrosis factor (TNF) (ref. Satoh J. et al, J. Clin. Invest. 84, 1345-1348 (1989), Satoh J. et al, J. Immunol. 145, 1395-1399 (1990) and Seino H. et al, Clin. Exp. Immunol. 86, 413-418 (1991)) which are cytokines, suppressed the induction of cytotoxic lymphocytes which damage .beta.-cells in the pancreas (ref. Shintani S. et al, J. Immunol. 144, 136-141 (1990)), so that the administration could protect the development of Diabetes in NOD mouse or BB rat.
On the other hand, NIDDM is characterized by a decrease in sensitivity to insulin, which is caused by a disorder of insulin production and secretion, existence of substances which suppress the action of insulin, a disorder of insulin receptors, a relative deficient of insulin by disorder of sites and signal transductions for insulin-action. Its complicated since it relates to both genetic factors and environmental factors. Obesity or aging is considered as an important factor which causes the decrease of sensitivity to insulin. As to a mechanism of the decrease of sensitivity to insulin, various disorders in some processes, from a process wherein insulin binds to the insulin receptors on the cell membranes to a process wherein the action of insulin is exhibited via a transmission of the information into cells, have been solving (ref. Kiyokawa Y. et al, Nippon Rinsho 1990 extra number, Diabetis Mellitus, Nippon Rinsho Press, Osaka 1990, p. 196-202).
Then, various agents as therapeutic agents for NIDDM, for example, (1) stimulants for synthesis of insulin and regulators for secretion of it as agents for disorder of the secretion and the production, (2) agents for absorption of sugar, stimulants for the utilization, agents for glucose transportor, or suppressors of gluconeogenesis in liver as agents for regulation of hyperglycemia, (3) stimulants for the action of insulin or antiglycation agents as a suppressor for disorder caused by hyperglycemia, and other anti-complication agents, have been developed, nevertheless, an effective therapy has not existed.
As the above mentioned, the mechanism of development of NIDDM is complicated, and an established theory of the mechanism thereof not has been obtained, a result, an effective protection against or therapy treatment for NIDDM has not been previously achieved.
Recently, it was found that hyperglycemia in an NIDDM model animal, KK-Ay mouse was normalized by bone marrow transplantation from a normal mouse (ref. Than S. et al, J. Exp. Med. 176, 1233-1238 (1992)) as well as allogeneic bone marrow transplantation to an IDDM model animal, NOD mouse could protect the development of Diabetes or inflammation of islets of Langerhans (ref. Nakamura M. et al, Diabetologia 3, 212-221 (1967) and Iwatsuka H. et al, Diabetologia 10, 611-616 (1974)).
An object of the present invention is to provide a therapeutic agent for NIDDM which is useful for immunological treatment in a short time or for a long time.